The human ITGAM gene variant rs1143679 has been recently identified as one of the strongest susceptibility factors for human systemic lupus erythematosus, or SLE. The ITGAM gene encodes for the CD11b subunit of complement receptor 3 (CR3). CR3 is highly expressed on immune myeloid cells and has important functions in cell adhesion, spreading, and migration. Furthermore, CR3 mediates complement-dependent phagocytosis of apoptotic cells (AC), and transmits immunosuppresive signaling following engagement by its ligands, such as the complement component C3bi. In this way, the complement system participates in the physiological clearance of AC and the maintenance of tolerance to self. Importantly, deficiencies in different complement components predispose to SLE. The current model envisions that defective AC clearance predisposes to post- apoptotic necrosis and spillage of intracellular inflammatory molecules, thus predisposing to inflammation and autoimmunity. However, results in mice deficient in receptors and molecules devoted to AC clearance have suggested that AC accumulation is not sufficient to cause lupus autoimmunity. We propose a novel, more comprehensive, model for SLE development, whereby defective AC uptake in combination with aberrant CR3- mediated immunosuppressive signaling synergize to promote a loss of tolerance and SLE development. The ITGAM gene variant rs1143679 causes an arginine to histidine (R77H) amino acid substitution in CR3, and has been associated with defective CR3-mediated phagocytosis of red blood cells and defective suppression of proinflammatory cytokine production by human macrophages. Despite the central importance of complement-dependent AC phagocytosis in the pathogenesis of SLE, to this date, AC phagocytosis and AC- mediated immunosuppressive signaling has never been investigated in R77H-bearing individuals. We aim to investigate whether the R77H substitution in CD11b/CR3 confers a potential defect in AC phagocytosis as well as defective suppression of proinflammatory cytokines production following CR3-mediated AC uptake. Furthermore, we are planning to dissect the molecular mechanisms underlying CR3-mediated suppression of cellular activation with the aid of biochemical studies, and to analyze whether the R77H substitution causes the disruption of CD11b/CR3-mediated suppressive signaling events leading to aberrant phagocyte activation. The identification of the molecular defects underlying the lupus susceptibility of individuals carrying the rs1143679 ITGAM variant will aid the design of novel therapeutic strategies aimed to bypass such defect via the specific targeting of the signaling molecules involved. Enhancing CD11b/CR3-mediated AC phagocytosis and suppressive signaling would promote the swift and immunologically silent clearance of apoptotic cells for the treatment and, possibly, prevention of autoimmunity in high-risk individuals carrying the mutated allele.